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The tragic loss of the prominent Dutch HIV/AIDS researcher, Joep Lange, M.D., Ph.D., 59, has been reverberating throughout the world since he and his partner, Jacqueline van Tongeren, perished with 296 others on Thursday when their Malaysia Airlines Flight 17 was shot down over Ukraine.

Lange and van Tongeren, a former HIV/AIDS clinical research nurse, had been flying from their home of Amsterdam to Kuala Lumpur on their way to the 20th International AIDS Conference in Melbourne, Australia.

An effort of the International AIDS Society (IAS), where Lange is a past-president, the conference was ahead of its time relative to those of other scientific organizations, "gather[ing] representatives of science, civil society, politics, and private sector to discuss together at an international level the most pressing issues linked to HIV/AIDS," as articulated by outgoing IAS president and Nobel laureate, Françoise Barré-Sinoussi.

Accounts of Dr. Lange's life have focused largely on his role at this level: the diplomacy of global HIV/AIDS prevention and treatment that required a firm, even hand in pulling together pharmaceutical companies, activists, government and NGO officials, health insurers, and patients themselves.

But how did he arrive at that level of prominence?

Recent visit to the U.S.

Michael Merson, M.D., Director of the Duke Global Health Institute (DGHI) and Wolfgang Joklik Professor of Global Health at Duke University, says that Lange's global efforts built on his early scientific and medical training at the outset of the AIDS pandemic. (Disclosure: I have held since 2002 an unpaid, adjunct faculty appointment in the Duke University School of Medicine.)

Merson was about a decade senior to Lange and had already spent 12 years with the World Health Organization when he became Director of the WHO Global AIDS Program in 1990. Leading a staff of over 500 in mobilizing the global response to the AIDS pandemic, Merson recognized a need to better focus the broad programs into two units.

In 1992, he recruited Lange as Chief of Clinical Research and Product/Drug Development, a position the Dutch physician-scientist held until 1995.

Lange directed several clinical trials, particularly with non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (Viramune; Boehringer Ingelheim). The work he led showed how the drugs could dramatically reduced mother-to-child HIV transmission, in some cases even with a single dose of nevirapine.

Merson has maintained his relationship with Lange to this day. Together with other colleagues, Lange just visited Duke in June to plan an initiative with DGHI researchers and clinicians.

Dr. Joep Lange during a June 2014 visit to the Duke Global Health Institute, Durham, NC. Dr. Lange is on the far left of the 2nd row, with Dr. Merson on the opposite right. Dr. John Bartlett, quoted below, is on the top row at the far right. Credit: Alyssa Zamora, Duke University Office of News & Communications.

HIV identified as the transmissible factor causing AIDS

Lange, a native of Nieuwenhagen, The Netherlands, earned his M.D. at the University of Amsterdam in 1981. After his internship, became immersed in the basic science of the clinical phenomenon of what became formally known as acquired immune deficiency syndrome.

The term, AIDS, was first used widely in a September 1982 report from the U.S. Centers for Disease Control and Prevention instead of other names that implied the disease was specific to homosexuals. We already knew that whatever caused the syndrome could be transmitted by blood transfusions and from infected mothers to their newborn infants.

In a section of her 2008 Nobel lecture entitled, "From Bed-side to Bench to Bed-side," Barré-Sinoussi encapsulated the field's environment when Lange first came on the scene:

"These early years of HIV research were the reflection of clinical observations, which prompted basic research in the laboratory, which in turn resulted in the development of clinical tools."

Barré-Sinoussi first published in May 1983 with Luc Montagnier on their isolation of the new retrovirus that was later shown to cause AIDS.

Dr. Merson further described the scene on the ground, "If you go back to the mid 80s and early 90s,- say, the first 15 years of the pandemic – what you have now are a group of people in their 50s, 60s, or even 70s. These were the people who fought so hard to get anything done – a new disease, you had people dying like crazy – and you built a kind developed a camaraderie."

"Joep, of course, was on the frontier of all this. This was the Belgian-French group. They had a lot of young people working in Africa, many who died – young physicians – because they didn't know what this was. "

Lange's very first peer-reviewed publication in 1984 in The Lancet, shows how clinicians were reaching for anything and everything to manage odd infectious diseases being seen in homosexual men and Europeans from Central Africa.

The paper describes pulling out all the stops for two men with life-threatening intestinal parasite infections that were causing diarrhea at a rate up to 7 liters per day:

"The diarrhoea was so devastating that, with the patient’s informed consent we decided to try amprolium, a drug successfully used in chicken and calves with coccidiosis."

The veterinary drug, amprolium, was sold by then Merck, Sharpe and Dohme, and continues to be sold today in 10 kilograms bags for livestock parasite prevention.

The patients recovered from their intestinal disease but one ended up succumbing to a form of pneumonia (PCP) caused by another re-emerging organism at the time, Pneumocystis cariini. The other patient experienced some severe neurological side effects but was still alive and mobile at seven months, when the report was published.

Critical, early scientific contributions

Among Lange's impressive record of over 400 publications, over a dozen were cited in more than 100 other research publications. The extent to which one's work is cited in other publications is a significant indicator of one's impact on a research field. Most researchers would be delighted to have two or three of these in their careers.

Upon completing his Ph.D. work in 1987, Lange's top three most highly-cited papers became regarded among his most important scientific contributions, according to John A. Bartlett, M.D., co-director of Duke's Center for AIDS Research and Professor of Medicine at the Kilimanjaro Christian Medical Centre in Moshi, Tanzania.

Bartlett wrote in an email exchange, "In terms of Joep's early career, I think that his contributions to understanding the pathogenesis of HIV infection were very significant, and quite formative to his opinions regarding treatment. He believed passionately in the use of multiple drugs to inhibit virus replication, and that if you were successfully in stopping virus replication, the clinical progression of the disease would be stopped."

By "pathogenesis of infection," Dr. Bartlett means that Lange and his colleagues figured out the timeline and progression of effects on the body from quiet viral infection until patients exhibited devastating consequences.

This progression to what's called "full-blown AIDS" in popular language refers to the path of patients with no symptoms to when their immune systems can no longer respond to other infectious diseases seen rarely in people with the normal ability to fight off bacterial, fungi, and other viruses.

The first of these papers, published in the Journal of Clinical Investigation in 1988, examined 14 men who tested positive for HIV for at least two years but who did not yet have clinical AIDS itself, as defined by a substantial decline in the number of T-cells carrying a marker called CD4.

Remember that PCR gene amplification techniques were only coming into their own when these studies were conducted. So, the investigators defined patients as "seropositive" when they were found to have antibodies to proteins made by HIV. These antibodies indicated that the patients had been exposed to HIV.

Lange and colleagues showed that other components of the immune system were being attacked before a drop in CD4-positive T-cells could be observed. Specifically, other immune cells called B cells were already compromised in their ability to make antibodies in general, and were stunted when experimentally-stimulated to make antibodies.

Why was this important to know? Suppression of these other immune cells meant that the virus was already doing its dirty work and not just quietly resting. The first drug specifically targeting the virus, zidovudine, then known as AZT, was only just being approved in the U.S. in 1987.

While AZT and subsequent drugs were being reserved for patients with substantially decreased numbers of CD4+ cells, the work of Lange and colleagues provided a strong basis for the idea that patients should receive antiretroviral drugs long before they have disease symptoms.

The second paper, published in the Journal of Virology in 1989, examined how the virus changed in 20 patients during their progression from no symptoms to full-blown immunodeficiency. Here, Lange and colleagues showed that the rate of HIV replication, the rate at which new viral particles are produced, is absolutely crucial to the massive drop in CD4+ T-cells.

Lange had to take patient blood samples back to the lab and look at how the virus behaved in infecting normal blood cells taken from other patients. For the first time, they were able to show that when the virus increased its rate of replication, the patients CD4+ T-cells started going down. Those patients with low rates of viral replication were delayed in taking big hits to their T-cell numbers. But because their genetic tools were somewhat crude at the time, they could not identify what triggered the virus to become activated.

The third paper, also published in the Journal of Virology but around the time he joined the WHO in 1992, has been cited over 1,000 times. More remarkably is that it continues to be cited in research published today, 22 years later.

Here, they showed that the virus was hiding in other infection-fighting white blood cells called monocytes and macrophages. In particular, the macrophages could harbor HIV outside the blood, off in tissues. That fact that huge reservoirs are HIV were churning about in other blood cells and outside the blood before a patient had symptoms provided even more evidence that they should get the new HIV drugs to prevent full-out disease.

"I remember in meetings with him and he was one of the first to push early treatment. He really believed the science was strong for early treatment and he was upset it took so long to get there," said Merson.

Lange's insistence on this approach continues today, albeit in his absence, but for early treatment in the developing world. In a paper published just three weeks ago, he reiterated his argument that overcoming the burden of upfront drug costs was worth the long-term gains:

"[T]reatment as prevention should be understood as the early initiation of ART [antiretroviral drug therapy] to prevent disease progression, opportunistic infections, and premature death. Secondarily, it also prevents HIV transmission and reduces HIV incidence."

In a subsequent piece, we'll take up Lange's post-WHO contributions that illustrate his impact outside the laboratory and clinic.

I always welcome any comments but, today, especially those from anyone who knew Dr. Lange or who works in the HIV/AIDS field in general.